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In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K - PLoS ONE (2010)

Bottom Line: However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain.On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

ABSTRACT

Background: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers.

Methodology/principal findings: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.

Conclusions/significance: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

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Related in: MedlinePlus

Time-activity curves of radioactivity in four brain regions (frontal cortex, thalamus, hippocampus, and cerebellum) and metabolite corrected plasma after intravenous injection of [11C]A-844606 in baseline and SSR180711-blocking PET scans.The monkey was given intravenously saline and SSR180711 (5.0 mg/kg, i.v.) in the baseline (filled symbols) and SSR180711-blocking (open symbols) scans, respectively, 30 min after injection of [11C]A-844606. Radioactivity was expressed as a percentage of injected doses per ml of tissue (%ID/ml).
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pone-0008961-g005: Time-activity curves of radioactivity in four brain regions (frontal cortex, thalamus, hippocampus, and cerebellum) and metabolite corrected plasma after intravenous injection of [11C]A-844606 in baseline and SSR180711-blocking PET scans.The monkey was given intravenously saline and SSR180711 (5.0 mg/kg, i.v.) in the baseline (filled symbols) and SSR180711-blocking (open symbols) scans, respectively, 30 min after injection of [11C]A-844606. Radioactivity was expressed as a percentage of injected doses per ml of tissue (%ID/ml).

Mentions: Figures 4 and 5 show the static and VT images of [11C]A-844606, and their TACs, respectively, in a monkey brain in baseline and SSR180711-blocking conditions. The blocking effect by pretreatment with SSR180711 was visualized much more clearly in the VT images than in the static images. At baseline, the radioactivity in three of the four brain regions increased gradually over 90 min, with the exception being the cerebellum, where the radioactivity reached a plateau at 40 min. Under the SSR180711-blocking condition, the accumulation of radioactivity occurred slightly more quickly, reached a plateau at 40–60 min, and then decreased slightly. Both the total and metabolite-corrected plasma radioactivity decreased rapidly (data not shown).


In vivo evaluation of alpha7 nicotinic acetylcholine receptor agonists [11C]A-582941 and [11C]A-844606 in mice and conscious monkeys.

Toyohara J, Ishiwata K, Sakata M, Wu J, Nishiyama S, Tsukada H, Hashimoto K - PLoS ONE (2010)

Time-activity curves of radioactivity in four brain regions (frontal cortex, thalamus, hippocampus, and cerebellum) and metabolite corrected plasma after intravenous injection of [11C]A-844606 in baseline and SSR180711-blocking PET scans.The monkey was given intravenously saline and SSR180711 (5.0 mg/kg, i.v.) in the baseline (filled symbols) and SSR180711-blocking (open symbols) scans, respectively, 30 min after injection of [11C]A-844606. Radioactivity was expressed as a percentage of injected doses per ml of tissue (%ID/ml).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813863&req=5

pone-0008961-g005: Time-activity curves of radioactivity in four brain regions (frontal cortex, thalamus, hippocampus, and cerebellum) and metabolite corrected plasma after intravenous injection of [11C]A-844606 in baseline and SSR180711-blocking PET scans.The monkey was given intravenously saline and SSR180711 (5.0 mg/kg, i.v.) in the baseline (filled symbols) and SSR180711-blocking (open symbols) scans, respectively, 30 min after injection of [11C]A-844606. Radioactivity was expressed as a percentage of injected doses per ml of tissue (%ID/ml).
Mentions: Figures 4 and 5 show the static and VT images of [11C]A-844606, and their TACs, respectively, in a monkey brain in baseline and SSR180711-blocking conditions. The blocking effect by pretreatment with SSR180711 was visualized much more clearly in the VT images than in the static images. At baseline, the radioactivity in three of the four brain regions increased gradually over 90 min, with the exception being the cerebellum, where the radioactivity reached a plateau at 40 min. Under the SSR180711-blocking condition, the accumulation of radioactivity occurred slightly more quickly, reached a plateau at 40–60 min, and then decreased slightly. Both the total and metabolite-corrected plasma radioactivity decreased rapidly (data not shown).

Bottom Line: However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain.On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

ABSTRACT

Background: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers.

Methodology/principal findings: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.

Conclusions/significance: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain.

Show MeSH
Related in: MedlinePlus